Improving the diagnosis of pulmonary tuberculosis in hard-to-reach patients in London, UK
Developed countries have not escaped the rise in cases of multidrug-resistant tuberculosis. In the UK a mobile X-ray unit has been operating in London since 2005 and this service has been augmented with point-of-care testing (POCT) since 2011. POCT has been well received by patients and has greatly reduced the number of unnecessary hospital visits.
by Dr R. J. Shorten and Dr A. Story
Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis. TB is primarily a respiratory disease, although it can affect any part of the body and it is spread from person to person via expectorated droplets by individuals with active pulmonary disease. TB is a significant international problem and in 1993 the World Health Organization declared tuberculosis a global emergency . In 2012 there were 8.6 million new cases and 1.3 million deaths, the vast majority of these occurring in Asia and sub-Saharan Africa .
This global epidemic is further complicated by the increase in drug resistant M. tuberculosis. Multidrug-resistant TB (MDR-TB) is a form of TB caused by bacteria that do not respond to, at least, isoniazid and rifampicin, the two most effective, first-line anti-TB drugs. There were approximately 450 000 cases of MDR-TB globally in 2012. More than half of these cases were in India, China and the Russian Federation .
This epidemic has not been avoided in developed countries and following a century of decline, the incidence of TB in the UK has been rising since 1988. Data from Public Health England  shows that the majority of these cases are concentrated in urban areas, with almost 40% being in London (3426 cases in 2012). Additionally, one or more of the following risk factors were present in 7.3% of cases; history of problem drug use, alcohol misuse/abuse, homelessness or imprisonment. Furthermore, some of these individual risk factors are associated with smear positivity (those patients who are more likely to be contagious), drug resistance, poor adherence to treatment and loss to follow up . Indeed, the growing problem of TB in these hard-to-reach groups has led to specific UK guidance .
Searching for patients
Find & Treat was established in 2005 to strengthen TB control in the socially excluded communities of London by working with over 200 partner organizations. The service has been evaluated as an innovative and cost-effective health and social care model . The mobile X-ray unit (MXU) has been operating in London since this time and screens approximately 8000 patients per year (Fig. 1). It is staffed by TB nurse specialists, reporting radiographers, social workers and outreach workers and former TB patients with a lived experience of homelessness who work are Peer Educators. Its role is to identify hard-to-reach patients with suspected TB using digital chest radiographs. These patients are then linked into local healthcare provision via Accident & Emergency (A&E) departments or community TB programmes. In December 2011 the service was augmented with the Xpert MTB/RIF assay (Cepheid, Sunnyvale, California, USA), which was used as a point-of-care test (POCT) for the molecular detection of M. tuberculosis in sputum .
Prior to the implementation of the Xpert assay, if a digital chest radiograph indicated active pulmonary TB (seen in 1–2% of patients screened), then the patient underwent immediate referral to the nearest hospital with a TB service. This involved a TB nurse specialist or outreach worker accompanying the patient to an A&E department for assessment, conventional microbiological investigation and possible admission. Approximately 20% of referred patients are subsequently confirmed to have TB and are initiated on a complex course of multiple antibiotics over a period of at least 6 months .
The Xpert MTB/RIF assay is a nucleic acid amplification test (NAAT). The easy to use analyser extracts, amplifies and detects DNA of M. tuberculosis in the patients’ sputum. The assay also detects approximately 95% of the common rifampicin resistance-conferring mutations in the rpoB gene (a surrogate marker of multidrug resistant TB) .
The hands-on time of the assay is minimal and a specimen container with a rubber septum in the lid allows the staff on the MXU to safely process sputum samples without the need for containment facilities or a microbiological safety cabinet (Fig. 2). MXUs exist in other European cities, but we believe that this is the first example of a NAAT POCT being used in this way anywhere in Europe.
Patients with abnormal X-rays that indicate active pulmonary TB are asked whether they can produce sputum. Those who can, expectorate a sample into the specific sample container. They seal the container and return it to the team on the MXU who assess the sputum for quality (sputum, rather than watery saliva is required). The sample reagent is carefully added through the rubber septum in the lid and swirled gently to allow homogenization of the sample. This process ensures that minimal aerosols are generated and that they are not released to cause exposure to the operator. The assay takes approximately 2 hours in total and the result will determine whether the patient requires immediate referral to a TB service. Patients with negative NAAT are followed up by two further sputum samples, including one early morning specimen, collected in the community and processed for routing smear microscopy and culture in hospital laboratories. Due to the high negative predictive value of the assay (94%) and the increased sensitivity compared to sputum microscopy , it is highly unlikely that any infectious cases will go undetected using this algorithm.
Considerations and advantages of POCT for TB
As the POCT is performed by non-laboratory staff, it is imperative that the MXU staff are comprehensively trained and assessed for competence. None of the staff had any laboratory or analytical experience prior to the implementation of this assay. Registered clinical laboratory staff are involved in all stages of implementation and training. A close working relationship between the MXU team and the clinical laboratory is required to ensure appropriate refresher training and review of standard operating procedures and risk assessments.
The assay has been well received by patients, particularly as a negative result prevents a referral to hospital. This allows MXU staff to focus resources on screening more patients, rather than accompanying patients to hospital who subsequently are confirmed to be clear of TB. The MXU regularly screens in custodial settings where capacity to effectively isolate suspected cases is limited and significant resources are required accompanying patients with suspected TB to hospital appointments for further investigations. The value of the assay in determining which patients are potentially infectious is especially useful in these settings. The ability of the Xpert MTB/RIF to detect most cases of rifampicin resistant (and therefore likely to be MDR) TB, allows the MXU team to initiate appropriate second-line therapy more rapidly. Additionally, the simplicity and safe use of the assay has been well adopted by the MXU staff. We have demonstrated the potential of this technology in focussing resources on the most appropriate individuals and therefore improving the quality of care in this vulnerable group of patients. A randomized controlled trial to assess the benefit of using this assay on patients with an abnormal chest X-ray against them being referred to secondary care is underway to accurately quantify the benefits of this assay in tackling TB in this group of patients.
The epidemiology of TB in 21st century big cities is characterized by a concentration of disease in hard-to-reach medically underserved populations. Capacity to outreach effective diagnostic platforms directly to high risk populations is likely to become an increasingly important feature of TB control .
1. World Health Organization (WHO). Tuberculosis. Fact sheet 104, 2012. 2. WHO. Tuberculosis. Media centre; Fact sheet 104, 2014.
3. Tuberculosis in the UK: Annual report on tuberculosis surveillance in the UK, 2013. London: Public Health England 2013.
4. Story A, Murad S, Roberts W, et al. Tuberculosis in London: the importance of homelessness, problem drug use and prison Thorax 2007; 62(8): 667–671.
5. National Institute for Health and Clinical Excellence (NICE): Public health guidance. Tuberculosis – hard-to-reach groups. PH37 2012.
6. Jit M, Stagg HR, Aldridge RW, et al. Dedicated outreach service for hard to reach patients with tuberculosis in London: observational study and economic evaluation. BMJ 2011; 343: d5376.
7. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010; 363: 1005–1015
8. NICE: Clinical guidelines. Tuberculosis: Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. CG117 2011. (http://guidance.nice.org.uk/CG117)
9. Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis. Int Tuberc Lung Dis. 2009; 13(11): 1320–1330.
10. O’Grady et al. Evaluation of the Xpert MTB/RIF assay at a tertiary care referral hospital in a setting where tuberculosis and HIV infection are highly endemic. J Clin Infect Dis. 2012; 55(9): 1171–1178.
11. van Hest NA, et al. Tuberculosis control in big cities and urban risk groups in the European Union: a consensus statement. Euro Surveill. 2014;19(9): Article 7.
Rob J. Shorten1* BSc, MSc, PhD and A Story2 RGN MPH PhD
1Clinical Scientist, Department of Medical Microbiology, Central Manchester Foundation Trust and Honorary Research Associate, University College London Centre for Clinical Microbiology, UK
2Clinical Lead Find & Treat, University College Hospitals NHS Foundation Trust, London, UK